The Nucleus Accumbens (NAc) is implicated in craving, reward and reinforcement of alcohol drinking. The NAc/Striatum expresses the highest levels of high affinity adenosine A2A receptors in the central nervous system (CNS) and is characterized by co-expression of A2A with dopamine D2 receptors (D2) on the same neurons. We have evidence that subthreshold concentrations of the D2 agonist NPA and ethanol, that have no effect alone, act synergistically when added together to stimulate PKA signaling. Synergy requires bettayamma, dimers and A2 receptors. Neurons that express D2 and A2 on the same cells, as in the NAc, are simultaneously hypersensitive to ethanol in the presence of dopaminergic tone and hypersensitive to D2 signaling in the presence of ethanol. Synergy may play a role in ethanol consumption. Expression of a beta/gamma, inhibitor in NAc reduces voluntary ethanol consumption. Our hypothesis is that unique and specific signaling components are responsible for synergy between D2 and ethanol/A2 in NAc/striatal neurons and that these molecules regulate drinking behaviors. The overall goal of this project is (a) to identify the specific molecular signaling components in NAc/Striatal neurons which regulate ethanol-induced increases in PKA signaling and reinforcement of ethanol consumption, and, (b) to develop new therapeutics for alcoholism. Our specific aims are: I: Identify specific G-protein components responsible for synergy between ethanol and NPA for activation of PKA signaling; Il: Test whether a specific activator of G protein signaling, AGS3, selectively regulates synergy between D2 and ethanol; III: Test which specific beta/gamma dimers released upon D2 activation activate adenylyl cyclase II and/or IV in primary striatal neurons; and IV: Test the role of the ethanol/A2 and D2 signaling components in ethanol operant self-administration and in CNS responses to ethanol. The experiments in this proposal will identify and validate novel targets for the development of new therapeutic agents to treat alcoholism and alcohol abuse.